QUANTITATIVE STUDIES ON CONCURRENT FACTORS IN NEOPLASTIC TRANSFORMATION

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Studies on mechanisms of transformation in the mouse embryo BALB/3T3 clone A-31-1-1 cell line were continued. (1) Transformation was obtained with several metals. The mechanisms of toxicity and transformation by both trivalent and pentavalent arsenic (As) were investigated. Trivalent As was found to be 4 times more active than pentavalent As. Cellular uptake was higher for trivalent form by a metabolic reduction process partly dependent on glutathione. When correlated with the calculated As cell burden, toxicity and transformation frequency were found to be the same for both forms of As. Cells exposed to pentavalent As released the trivalent form into the medium. No methylated metabolites were found, indicating lack of this detoxification mechanism in this cell line. The results indicate that trivalent As is the form responsible for the toxic and transforming effects, independent of the valence state of the As exposure. (2) Previous studies on the induction kinetics of ouabain- resistant mutations induced by N-ethyl-N-nitrosourea in BALB/3T3 cells were repeated and fully confirmed using larger numbers of cells. (3) When inoculated in nude mice, BALB/3T3 cells transformed by As, by other carcinogens, or spontaneously, were found to be tumorigenic but not metastasizing, in keeping with the lack of type IV collagenolytic activity observed in these cell lines. Induction of metastatic activity by further treatment with the ras oncogene or with carcinogens in under investigation.